University of Groningen
Organic reactivity in mixed aqueous solvents
Blokzijl, Wilfried
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to
cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
1991
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Blokzijl, W. (1991). Organic reactivity in mixed aqueous solvents: a link between kinetics and
thermodynamics s.n.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the
author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately
and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the
number of authors shown on this cover page is limited to 10 maximum.
Download date: 15-06-2017
I . Introduction Solvent gects on organic reactions in aqueous mirtwes
CHAPTER 1
Solvent Effects on Organic Reactions in Aqueous Mixtures.
An Introduction
2.1 Solvent effects in chemistry
2.1.1 Some words about the hirtorical background
Reactivity of molecules and ions in solution is largely dictated by the solvent. Comparison of rate constants in the gas-phase and in solution shows that differences of 10"
are not uncommon1. In 1862, Berthelot and PCan de Saint-Gilles were the first to
notice the considerable influence of the reaction medium on the rates of homogeneous chemical reactions2. In 1890, Menschutkin performed the first detailed study of
the reaction of trialkylamines with haloalkanes in twenty-three different solvents and
stated that "solvents are by no means inert in chemical reactions and can greatly
influence the course of themN3.Since then many papers have appeared in which more
or less dramatic solvent effects are reported on a large variety of chemical processes.
Changing the solvent can, in extreme cases4, lead to rate variations in the order of
lo9. Not only chemical reactions, but also chemical equilibria are sensitive to the
solvent. This was shown by ClaisenS and wislicenus6, who were, in 1896, among the
first authors to draw attention to the considerable solvent effect on keto-en01
tautomeric equilibria. The fact that the solvent can seriously affect spectroscopic
properties of molecules in solution was demonstrated by ~ u n d t 'in 1878. During the
past century, solvent effects have also been reported on a number of other chemical
phenomena, such as aggregation8, complexation9, ionisationlo, conformation" and
isomerisation12. Solvent effects on chemical reactivity have received close attention. A
long-lived goal of chemists at large has been to establish methods and to provide tools
to understand and predict solvent effects on chemical reactions. Ultimately, this
knowledge should enable chemists to choose in a rational way a suitable solvent for a
particular chemical transformation.
1.1.2 W a r ; menstruum univer~ale?'~
According to ancient Greek philosophy every solution was called "water" and all
liquids, able to dissolve compounds were classified as "divine water". Water was in fact
the first liquid to be considered a solvent. Many publications and textbooks claim that
water is in every aspect a unique solvent and liquid. Water certainly is the most
extensively studied liquid. Properties, models and theories have been discussed in
detai114-16.Although living organisms depend in a unique way on water as a solvent for
biochemical transformations, synthetic organic chemists do not particularly like water
1. Introduction Solvent effects on organic reactions in aqueous mixtures
Table 1-1:Summary of organic reactions performed in homogeneous and heterogeneous aqueous media.
Reaction
References
Intermolecular Diels-Alder reactions
Intramolecular Diels-Alder reactions
Claisen rearrangements
18f,g
Aldol reactions of silyl-en01 ethers
19c
Benzoin condensation
17e
Reduction of alkyl halides with tinhydride
17f
Allylation of carbonyl compounds using zinc
22a,b, 29
as a solvent for chemical reactions. This "hydrophobic" attitude stems largely from the
fact that water is far from a "Menstruum Universale" for organic compounds.
Moreover, water is often highly reactive towards many organic reagents. Nevertheless,
the past decade has witnessed a remarkable reappraisal of water as a solvent for
organic reaction^'^-^^. This change in attitude is partly due to the pioneering work of
res slow"", who, in 1980, reported intriguing solvent effects of water on notoriously
solvent-insensitive Diels-Alder reactions. This discovery inspired others to search for
other organic reactions that could benefit likewise from water as a solvent. In
addition, the need for solvents that can satisfy the high requirements of current
environmental legislation, makes water an interesting choice as a solvent for organic
reactions. In Table 1-1 a collection of organic reactions is surnrnarised that are not
traditionally performed in water, but were found to benefit from the presence of
water as a solvent. The molecular origin of these remarkable and sometimes even
spectacular solvent effects in aqueous solution remains unclear.
1.2 A survey of approaches to the analysh of solvent
effect^^'-^^
Solvent effects on chemical processes are usually studied in comparison to reactivity in
a reference solvent. In some cases comparison is made with gas-phase reactivity.
Generally, analysis of solvent effects has been based on an equilibrium solvation
model. However, for some organic reactions the reaction rates can be very high and
examples are known for which non-equilibrium or dynamic solvation models have to
be used to account for reactivity in solution. Consequently, sophisticated theoretical
models have been developed. In the past, quantitative and qualitative approaches for
the analysis of solvent effects have been developed almost simultaneously.
1. Introduction Solvent effects on organic reactiom in aqueous mixtures
Qualitative descriptions of solvent effects. Almost all qualitative treatments of solvent
effects are based on the simple solvation model, developed by Hughes and Ingold in
1935, for explaining solvent effects on substitution and elimination reactionsB. The
model considers mainly the change of electrical interactions between solvent and
reacting species during the activation process. Solvents are thus classified according to
their ability to solvate ions and molecules. A serious shortcoming of this approach is
the fact that the solvent is considered as a continuum without defined structure and
that specific solvent-solute interactions are completely neglected. In addition, changes
in the structure of solvents as a result of changes in solvation during the activation
process are neglected. Also entropic contributions to solvent effects are not incorporated into this model. Especially in highly structured solvents such as water, entropic
contributions to solvent effects can be significant. Notwithstanding the weak points of
these qualitative models, these approaches are simple and are readily applied; they
are still very popular in practical chemistry.
Quantitative descriptions of solvent effects. The starting point of most quantitative
approaches for the interpretation of solvent effects is based on transition state theory
(TST). A general quantitative description of solvent effects is given in Equation 1-1,
in which
A pi,= pic(S)
-
P ~ H )
and
where ApIsO and ApACOare the transfer standard chemical potentials of the initial state
and the activated complex, respectively, for transfer from the reference solvent R to
solvent S. The rate constants, found in solvents S and R are k and k,, respectively.
The success of any quantitative method in describing solvent effects is determined by
the accuracy with which the Gibbs energies of solvation can be calculated. A detailed
knowledge of solvent-solute interactions is essential for this goal. The wide range of
possible solute-solvent interactions, the actual structure of the solvent, the characteristics of the reacting molecules and the activated complex make enormous demands on
the theory. (Semi)quantitative approaches can be subdivided into four major categories:
(i)
(ii)
(iii)
(iv)
Correlations with physical properties of the solvent.
Correlations with empirical solvent parameters.
Analysis incorporating solubility andfor transfer parameters.
Theoretical treatment of solute-solvent interactions.
In separate sections, these approaches will be briefly outlined and critically discussed.
1. Introduction Solvent pffects on organic reactions in aqueous rnirtures
1.2.1 Correlations with physical properties of the solvent
Solvents can be classified according to many physical properties. Some of these have
been used for the correlation of solvent effects. Frequently, the justification for these
correlations is found in some theoretical model. Most popular are correlations with
the relative permittivity, E, of the solvent. Solvent effects are often related to
functions like [(~;l)/(&,+l)] or I/&,. The theoretical basis for these correlations has
been given by Eyring, Kirkwood, Laidler and ~andskroene?"'. Another well-known
method, developed by Scatchard and Hildebrand, is based on the energy of evaporation of a solvent per unit of volume, the cohesive pressure or cohesive energy density, c
or aH2384. Related to this approach are correlations with the internal pressure of the
solvent42,-rr. These methods are mainly used to analyse solvent effects on reactions
between neutral molecules. Koppel and palm4' emphasised the importance of the
polarisability of the solvent, which can be expressed by a function of the refractive
index of the solvent, [(n2-1)]/[p2+l)]. In this light, also correlations with the polarisability parameter P are known4 744. Finally, correlations with the viscosity of the solvent
have been used to explain solvent effects on diffusion-controlled reactions45746.
Correlations of solvent effects with these solvent parameters are often surprisingly
good. The inherent weakness of the method is that the parameters measure macroscopic properties. Specific solute-solvent interactions that occur on a microscopic scale
are completely neglected. The structural changes of the solvent, accompanying the
activation process, are also neglected. Correlations with physical properties of the
solvent are mainly associated with enthalpic contributions to the overall solvent effect,
which makes the method less suitable for reactions in highly structured solvents such
as water.
1.2.2 Correlations with empirical and semi-empirical solvent parameters
The ability of a solvent to solvate molecules or ions, sometimes rather ambiguously
described as the solvent polarity, is difficult to express in terms of physical solvent
parameters. This problem forced chemists to search for empirical or semi-empirical
scales of solvent polarity. The list of solvent polarity scales is long and lengthens every
yea?.'
The scales are based on linear solvent energy relationships (LSER) and use
solvent effects on properly selected model processes. In the literature, correlations
involving solvent polarity parameters are frequently encountered. Some polarity scales
have found a wider application in the analysis of solvent effects and will be described
briefly below.
Most popular polarity scales are based on spectroscopic properties. Spectroscopic
data describing solvent effects on UVIVIS transitions of a large number of solvatochromic dyes resulted in a long list of solvatochromic polarity parameters4'. One of
the oldest parameters, introduced by ~ o s o w e r ~ ' in
. ~ ~1958, the Z-value, is still
frequently used. Dimroth and ~ e i c h h a r d t ~ ' reported
~'
probably the best known and
most frequently used solvent polarity parameter, the q 3 0 ) value. The standard
probe molecule is a pyridinium-N-phenoxide betaine dye (I), which has a T-T'
absorption band with intramolecular charge-transfer characteristics.
I. Introduction Solvent effects on organic reactions in aqueous miaures
This parameter can be determined in many solvents and is very solvent sensitive.
Another series of parameters, based on spectroscopic transitions was introduced by
~.~~.
Kamlet, Taft and Abraham and is related to specific properties of the s o l ~ e n t ~The
a-scale measures the hydrogen bond donor acidity of the solvent, the p-scale the
hydrogen bond acceptor basicity of the solvent and the T*-scale the polarisability or
dipolarity of the solvent. The a-scale and the p-scale are based on a solvatochromic
comparison method, using solvatochromic shifts of 6nitroaniline and N,N-diethyl-4nitroaniline. Similarly, the T-scale is based on electronic T-T* transitions of seven
nitroaromatics. The Acceptor Number (AN), introduced by Gutmanns4, is based on
the relative 3 1 ~ chemical
~ shift
~
values
~
of triethylphosphane oxide related to those
of the 1:l adduct Et,PO-SbC15. The scale classifies the solvent according to Lewis
acidity or the Electron Pair Acceptor property of the solvent.
A few solvent polarity scales have been related to chemical equilibria. The Donor
Number (DN) measures the Lewis basicity of the solvent'0JS~s6.SbCls was used as a
reference compound. The parameter is defined by the enthalpy associated with the
adduct formation between antimony pentachloride and Electron Pair Donor solvents.
The oldest polarity scales find their origin in kinetic measurements. A famous
~ expressed
example is the ionising power, as defined by Winstein and ~ r u n w a l d 'and
in the solvent Y-scale. This scale has been developed on the basis of the rate constant
for the SN1 solvolysis of t-butylchloride in different solvents. Later, this approach was
' , others6' in order to extend the procedure to
modified by winstein*', ~ e n t l e g ~ ' ~and
correlations of solvent effects on reactions involving borderline or even pure S,2
mechanisms.
Finally, a large number of polarity scales are based upon solubility data6', transfer
parameters6z63, partition coefficient^^^>^' and chromatographic
These
parameters quantify the phobicity or philicity of a selected compound for the solvent.
In physical organic applications the Hansch value^^*^^ as well as the S,-value,
recently introduced by brah ham^', are frequently encountered. Both parameters
measure the solvophobicity of apolar molecules for different solvents. Some empirical
parameters based on partition coefficients, solubility, and Gibbs energies of transfer
are mainly used in industrial and engineering applications.
I . Introduction Solvent effects on organic reactions in aqueous mixtures
The inherent weakness of these methods is that the solvent polarity scale is based
on a selected process and is therefore not universal. Obviously, only satisfactory
correlations can be expected for solvent effects on processes closely related to those
used to define the polarity scale. In addition, it is not always clear which of the many
types of solute-solvent interactions is expressed by a certain parameter. By careful
selection of the model process or by sophisticated comparison methods5z5396&70,
some
polarity scales have been given a relatively well-defined physical meaning. These
methods are based on the fact that some classes of compounds interact with the
solvent via a predominant and well-defined mode of interaction. A detailed interpretation of solvent effects in terms of specific interactions based on polarity scales is,
however, extremely difficult. The choice of a suitable solvent polarity scale to
correlate solvent effects on a new process is often simply pragmatic. A practical
limitation is that solvent polarity parameters often cannot be measured in all solvents.
It has become clear that no single solvent parameter can account for the complex
nature of solvent effects on different chemical processes. To circumvent this problem,
multiparameter approaches have been advocated. Koppel and palm7', and later
Kamlet, Taft and brah ham" and others71772
developed sophisticated multiparameter
equations, incorporating two to four empirical, semi-empirical or physical solvent
parameters. Selection of a set of independent solvent parameters that incorporates all
possible contributions to the overall solute-solvent interaction is rather arbitrary.
Every single parameter measures a combination of distinct contributions to the overall
solute-solvent interaction for which both the identity and magnitude are not properly
defined. An interpretation of the results of a linear regression analysis is difficult and
often highly speculative. From a more practical point of view, in particular for
predictive applications, the use of linear regression analysis is seriously limited by the
fact that for a proper calculation many datapoints are required. Finally, the theoretical
background of LSER's and its application as a tool to analyse or even predict kinetic
parameters for new chemical transformations, has been seriously criticised7'. Discussion of the fundamental aspects of LSER's is interesting and often philo~ophical~~.
1.2.3 Analysh of solvent effectsusing solubility and transfer parameters
Measurement of transfer parameters and solubilities to analyse solvent effects is
directly linked to the general Equation 1-1. Many techniques are available to measure
the standard chemical potentials and partial molar enthalpies and entropies of
transfer of compounds from one solvent to the ~ t h e r ~ ' -Transfer
~~.
parameters can be
used (i) to develop a solvent polarity scale or (ii) to determine the change in standard
Gibbs energy, enthalpy and/or entropy for the transfer of reactants for a particular
process. In the latter case, solvent effects can sometimes be analysed in terms of
initial state and transition state effects7'. In fact, measurement of transfer parameters
is the only way in which solvent effects can be analysed in terms of initial and
transition state effects. In some cases, initial state and transition state effects have
been subsequently analysed in terms of solvent polarity scales72.
In recent and interesting fundamental studies of reactivity in the gas phase,
reactants, present in the gas phase, are stepwise "solvated" by a. limited and accurately
1. Introduction Solvent effects on organic reactions in aqueous mirtures
known number of solvent molecules. The reactivity of these molecules in clusters is
monitored as a function of the number of solvent molecules present, and shows that
even a small number of solvent molecules can bring about a large change in reactivity77-79.Even with a limited number of solvent molecules, reactivity in the gas-phase
starts to resemble the reactivity in the condensed phase.
1.2.4 Theoretical treatments of solute-solvent interactions in rehation to solvent effeca
The past fifteen years have shown an impressive number of sophisticated theoretical
studies concerned with reactivity in the condensed phase. However, an unambiguous
and universal theory of the liquid state still does not exist. This fact strongly hampers
the theoretical treatment of reactivity in solutions. Early theoretical approaches were
mainly based on models of Kirkwood and O n ~ a g e P ~ ' ~ .
The first simulations of reactivity in solution appeared in the late sixties. The
accessibility of large computers and suitable quantum mechanical methods resulted in
a whole new area of theoretical studies of solvent effects. The first ab initio calculations of solvent effects were based on reactive com ounds, "solvated by a few solvent
molecules; the so-called super-molecule approachr2. These ab initio approaches are
still in the early stages of developments3. Other methods use quantum mechanical
approaches to calculate the reaction trajectories in the gas-phase, which are subseMolecular dynamics is used for
quently transfered into a box of solvent molecules84986.
allowing reacting systems to equilibrate with the solvent along the total reaction path.
Until recently only rather simple and elementary processes, like the substitution
reaction of chloromethane with chloride ion, have been studied in detail. Strikingly,
reactivity in water has received most attention.
Many theoretical studies are focused on non-equilibrium solvation. Conventional
transition state theory is shown to be unsuitable for the treatment of solvent effects in
these casess4. Among the topics which can be studied using modern computers are (i)
the time-scale of the reaction dynamics, (ii) the extent and importance of energy flow
from solvent to reactants and (iii) the involvement of the solvent dynamics in the
activation process. Recent calculation^^^ of the solvent effect on a S,Zprocess in
water show that water undergoes a substantial reorganisation well before the change
in the charge distribution of the reactants. This reorganisation appears to be crucial
for the overall reaction.
The development of theoretical models to calculate solvent effects is, however,
still in its infancy. Most methods do not take account of mechanistic changes that
might be induced by the solvent. The chemical processes, treated by theoretical
models, are necessarily still simple and elementary. Consequently, the results do not
yet attract the interest of experimental chemists. Unfortunately, the complexity of the
methods still creates a considerable gap between experimentalists and theoreticians. It
is striking that theoretical approaches of solvent effects do not appear in recent
reviews and textbooks on solvent effects in chemist$"32972. Apparently, reading
theoretical papers gives experimentalists, dealing with solvent effects, a genuine
feeling of dissatisfaction, which makes them turn to their familiar solvent polarity scales.
1. Introduction. Solvent effects on organic reactions in aqueous mi-s
1.3 Interactions and reactivity in water and in m h d aqueous solvents
Organic reactivity in water and in mixed aqueous solvents is determined by interactions of water and cosolvents or cosolutes* with the reactant(s) and the activated comp l e ~ Water-solute
~ ~ ~ ~ ~ interactions
.
reflect the fact that water molecules are small,
moderately polarisable and able to form a highly structured hydrogen bonded
network. Induced dipole-induced dipole interactions of water with solutes are small,
but the dipole moment of water does enable significant dipole-induced dipole and
dipole-dipole interactions with solutes. Obviously, an important contribution to the
overall solute-solvent interactions in water is hydrogen bonding. Finally, the interaction of water with charged solutes is very strong.
Hydrophobicity and hydrophobic hydration play an important role in the solvation
of reactants and activated complex in water and in mixed aqueous solvents. Hydrophobic effects are characterised by intriguing thermodynamic properties and are the
result of a combination of water-solute and water-water interactions. Traditionally,
hydrophobicity and hydrophobic hydration are considered to be a consequence of the
preference of water for interaction with other water molecules over interaction with
hydrophobic (i.e. apolar) solutes. In a study of solvent effects on reactions in aqueous
reaction media, a discussion of hydrophobicity and hydrophobic hydration is essential.
Recent views on these hydrophobic effects will be discussed in more detail in Section
1.4.
Interactions of reactant(s) and activated complex with cosolvent or cosolute
molecules in aqueous solutions involve all forms of dipolar interactions mentioned
above, but are strongly mediated by water. The thermodynamics of these interactions
strongly depend on the concentration of the solute molecules. In addition, hydrophobic interactions play a significant role in intermolecular interactions between solutes in
aqueous media. The interactions between hydrophobic compounds or hydrophobic
moieties in aqueous media is thermodynamically very complex, and some recent ideas
about hydrophobic interactions will be also outlined in Section 1.4.
1.4 Hydrophobic effects; &finitions and the state of the ad9-''
Hydrophobic effects; definition. Disagreements exist in the literature concerning the
definition of "hydrophobicity", "hydrophobic effects", "hydrophobic hydration" and
"hydrophobic interactions". The terms are strongly .related and some are practically
synonymous. Many different definitions for these terms can be encountered in the
literatures98. In order to prevent unnecessary ambiguities, a definition of these
hydrophobic terms will be given below.
The term "hydrophobic effects" describes all phenomena related to the dissolution
of non-polar solutes in aqueous media and is, as such, a quite general term. The term
"hydrophobicity" is ambiguous and many different interpretations are found in the
The definition of organic, irreactive compounds in aqueous media as cosolutes or cosolvents is
ambiguous. Following thermodynamic formalism, the term "cosolute" is more appropriate in dilute
aqueous media, whereas in binary aqueous mixtures the term "cosolvent"is prefered.
1. Introduction. Solvent effects on organic reactions in aqueous r n h r e s
literature. The extent of "hydrophobicity" can be expressed in an experimentally
accessible parameter measuring the solubility of apolar substances in waterg9. This
parameter involves (a) the breaking of the solute-solute interactions and (b) refilling
of the vacancy in the apolar medium, (c) creation of a cavity in the aqueous medium,
(d) onset of solute-water interactions and (e) rearrangement of the water molecules
surrounding the solute. Alternatively, "hydrophobicity" can be expressed in terms of a
transfer process of an apolar compound from an apolar solvent to water. In this case,
process (a) is replaced by breaking of the solute-solvent interactions.
The poor interactions between water and apolar solutes make the small but
significant solubility of completely apolar compounds in water rather unexpected.
"Hydrophobic hydration" has been suggested to account for this "high" solubility of
used the term "hydration
apolar compounds in water. Privalov and Gi111009'03J08~'09~111
effect" to describe this phenomenon. "Hydrophobic hydration" can be defined as the
combination of process (c), (d) and (e).
The term "hydrophobic interaction" seems to express the discomfort of chemists in
dealing with non-covalent interactions between apolar molecules in aqueous solution
that appear to be predominantly entropic in origin. It is necessary to make a clear
distinction between "bulk hydrophobic interactions" and "pairwise hydrophobic
interaction^"'^^^^^^. Unfortunately, this distinction is seldomly recognised in discussions
about hydrophobic interactions. "Bulk hydrophobic interaction" describes the tendency
of apolar molecules or moieties to form solvent unseparated clusters and can be
conveniently described as the reverse of process (a)-(e). "Pairwise hydrophobic
interaction" refers to the potential of average force between two hydrophobic solutes
in water, expressed in G(R), the gradient of which determines the force, necessary to
bring the two solutes S from an infinite distance to a distance R, as expressed in
Equation 1-292.
In this equation, Uss(R) is the solute-solute interaction potential, or the work required
to bring about the same process in vacuum. G~'(R)is the contribution of water to
the process in aqueous solution. This term is difficult to quantify and sometimes
refered to as hydrophobic interactiong2. The contribution of water to the process of
"bulk hydrophobic interactions" is even more difficult to establish experimentally. The
terms "hydrophobic hydration" and "hydrophobic interactions" are poorly defined in
the literature and the lack of a proper definition has resulted in discussions with a
strongly semantic f l a v o ~ r ' ~ ~ ~ ' ~ ~ .
Hydrophobic effects; the state of the art. The classical description of hydrophobic
hydration, as put forward by Frank and Evanslo4 in 1945 is still very popular. This
"iceberg model" was later quantified by Nemethy and ~cheraga"' and Frank and
wedo6. In 1959, hydrophobic interactions were introduced in a famous paper by
~ a u z r n a n n ~ These
~'.
four papers set the stage for later studies on hydrophobic effects.
Figure 1-1 shows the almost exponential increase of papers on hydrophobic effects
during the past 25 years. It is impossible to review in this thesis all theories and ideas
I . Introduction. Solvent fleets on organic reactions in aqueous m a r e s
about hydrophobic effects which have been presented in the literature during the last
decades. Emphasis will therefore be put on some novel and interesting developments.
Recently, the study of hydrophobic effects began to prompt a reconsideration of elder
t h e ~ r i e s ' ~ ~ An
~ ' ~important
~ ~ ~ ~ ' . reason for this development is the accessibility of large
computers and sophisticated models which have allowed detailed theoretical studies of
hydrophobic effects. Also experimental and theoretical studies of protein folding gave
a new impulse to the discussion about hydrophobic effects. "New views on hydrophobic effects" have been put forward that seriously contrast with classical descriptions112
l19. In this introducto~ychapter as well as in Chapter 8 new views on hydrophobic
effects will be compared to the classical theories on hydrophobic effects.
Hydrophobic effects are characterised by a number of remarkable features. The
most important feature of hydrophobicity, as expressed in the chemical potential of
transfer of a hydrophobic, apolar compound from an apolar phase to water, is the
unusual and large heat capacity ~hange"~*"~.
number of t i t l e s
year
Figure 1-1:Number of titles of research papers, containing the word "hydrophobic" as
a function of the year.
I . Introduction Solvent effects on organic reactions in aqueous mixtures
Consequently, partial molar enthalpies and entropies of transfer are highly temperature dependent.
The thermodynamic parameters, measuring the process of both pairwise and bulk
hydrophobic interactions, are also shown to be strongly temperature dependenta.
Privalov et a1.'00~103~108911'
reported methods to determine the thermodynamic quantities
of hydrophobic hydration, which are very difficult to measure experimentally, and
showed that hydrophobic hydration is characterised by a similar temperature dependence of enthalpy and entropy terms.
The classical model of hydrophobic effects is mainly based on phenomena
observed near room temperature. The hydration shell, surrounding apolar molecules
or moieties, is found to be highly structured, minimising the interactions between the
apolar molecule or moiety and water and optimising water-water interactions.
Detailed t h e o r e t i ~ a 1 ~ "and
~ ~ "computer
~~
simulation studies'22-'" confirmed that the
structure of the hydrogen bonded network of water is significantly altered in the first
solvation shell surrounding apolar molecules or moieties. The transfer of apolar
molecules from an apolar solvent to water is, at temperatures near 25"C, characterised by a positive standard Gibbs energy of transfer, a slightly negative enthalpy and a
large negative entropy of transfer*. For a broader temperature range, the thermodynamic parameters of transfer exhibit very characteristic values at two important
temperatures. At a temperature TH,which is near room temperature, the enthalpy of
transfer is nearly zero, whereas the entropy is strongly negative. At a temperature Ts,
which is near 160°C, the entropy of transfer is zero, and the enthalpy is highly positive"'. Apparently, the structure forming capacity of water is lost at these high
temperatures. The strong changes of AH0 and TASOas a function of temperature are
shown in Figure 1-2. The standard Gibbs energy of transfer, as indicated in Figure 1-2,
can be described by Equation 1-386~100~'01~'M~10808111.
A GwO = AH* - A Cp[(Ts- ;T)
+
T
1
In this equation, AH*,given by AC,(Ts-T,), corresponds to the enthalpy of transfer of
an apolar compound from the apolar liquid phase to water at T , and appears to
resemble the enthalpy of evaporation of the liquid, apolar solute. The second term on
the right, which is always negative, contributes favourably to the standard Gibbs
energy of transfer, and is strongly temperature dependent. This term can be identified
as due to hydrophobic hydration. Hydrophobic hydration apparently leads to a
decrease in the Gibbs energy of transfer. Both the enthalpy and entropy of hydrophobic hydration are strongly temperature dependent, but appear to be strongly compensating, leading to a small, but favourable overall Gibbs energy of transfer. At 160°C it
is definitely the unfavourable enthalpy of transfer AH*, which causes the large and
positive Gibbs energy of transfer of the apolar solutes from an apolar phase to water.
This unfavourable term has to be attributed to the disruption of London dispersion
interactions between the apolar solute molecules in the pure apolar, liquid state. At
room temperature, however, the loss of entropy determines the unfavourable Gibbs
energy of transfer. The loss of entropy, associated with the hydrophobic hydration of
the apolar molecules, is also accompanied by a similar gain of enthalpy. As a conse-
1. Introduction. Solvent effects on organic r e a c h m in aqueous mixtures
quence, the net Gibbs energy effect, associated with hydrophobic hydration, is very
small. In summary, the enthalpy and entropy of hydrophobic hydration strongly
moderate the enthalpy and entropy of transfer of apolar compounds from an apolar
phase to water, but hydrophobicity is caused by the enthalpically unfavourable
disruption of London dispersion interactions between the apolar solutes in the apolar
phase which are not restored by solute-water interactions. In fact, structural reorganisation of water around the apolar compounds decreases the propensity for London
dispersion interactions between the apolar solutes, and therefore increases the
solubility. This leads to the statement that the solubility of apolar molecules in water
is surprisingly large.
250
300
350
400
450
TIK
Figure 1-2: Standard Gibbs energy, partial molar enthalpy and entropy of transfer for
the transfer of an apolar liquid from its liquid state to water as a function of the
temperature. For simplicity, the temperature dependence of the heat capacity change
is neglected. Taken from ref. 108.
1. Introduction Solvent effects on organic reactions in aqueous rnirlures
This "new view on hydrophobicity" is mainly based on thermodynamic considerations. Recently, Lee has developed a model which accounts for the low solubility of
apolar compounds in water based on scaled particle theory as developed by Pierotti
and ~inanoglu'~-'~.
In this model the importance of the exceptionally small molecular
volume of water for the low solubility of apolar molecules in water is stressed. Linked
to this approach are studies in which the formation of a cavity in water is theoretically
modeled in order to gain more insight into the energetics of this process, which
appears to be entropically highly ~nfavourable'~'.The basic idea behind these models
is that a large number of small solvent molecules is restricted with respect to their
rotational freedom due to the presence in the solvation shell of an apolar solute.
The interaction of hydrophobic solutes in aqueous media is accompanied by the
overlap and merging of hydrophobic hydration shells. Near room temperature the
destructive overlap is accompanied by a gain of entropy and a loss of enthalpy.
However, the change of enthalpy and entropy, associated with this overlap term is
strongly temperature dependent. Based on the thermodynamic parameters of transfer
of apolar compounds from an apolar phase to water, Privalov and others have
concluded that hydrophobic interactions are, like the hydrophobicity, determined by
enthalpically favourable London dispersion interactions between the apolar solutes'O1*ll'. This is almost certainly the case for bulk hydrophobic interactions, which
lead to clusters of different size and morphology in the aqueous solution. The onset of
bulk hydrophobic interactions is often characterised by a critical concentration of the
solute, at which the formation of independent hydrophobic hydration shells, sufficiently effective to prevent association, has become impossible.
For pabvise hydrophobic interactions the problem is more complex. There has
been a tremendous growth in the application of empirical and ab initio intermolecular
potentials to model hydration processes. Recently, a host of papers has appeared in
which hydrophobic interactions are modeled extensively, using very sophisticated
theoretical models describing average potential forces between solutes in aqueous
have
solution. Studies by Chandler, Rossky, Karplus, Pettit and
revealed the existence of two clearly distinct configurations, which are separated by a
Gibbs energy bamer. These configurations are identified as (i) two apolar molecules,
separated by water and (ii) two apolar molecules in direct contact. The height of the
bamer and the relative importance of both configurations is not yet clear. Hydrophobic interactions have also been studied by theoretical analyses of the second virial
coefficients that appear in concentration expansion series describing thermodynamic
properties of aqueous solutions143.Second virial coefficients are experimental quantities. Model descriptions, which have been developed by Friedman and ~ r i s h n a n ' ~ ' ~ ' ~ ~
and later by
Franks'46, S ~ h e r a g a l ~Ben
~ ' ~ Nairn"
~,
and others14', were used
to interpret these quantities in more detail. In Chapters 2 and 3, some results of these
theoretical approaches of aqueous solutions will be discussed in more detail.
Nearly all recent theoretical studies of solvent-averaged forces between solutes in
water and some ab initio studies do agree that water decreases the attractive forces
between apolar solutes, compared to the interactions present in the gas-phase.
Notwithstanding the fact that not all theoretical models agree on this particular point,
most studies indicate a preference for solvent separated pairwise hydrophobic
interactions. However, the height of the barriers between contact and solvent
separated configurations remains unclear. The size of the solute appears to determine
1. Introduction Solvent effectson organic reactions in aqueous rniriwes
the height of the bamer. Recently, it has been shown that long-range attractive forces
are present between large apolar surfaces148.The molecular origin of these hydration
forces is also unclear.
1.5 The need for a quantitative description of solvent egects in mixed (aqueous) solve&.
Incenlives fir this study
In Section 1.2 it has been shown that simple quantitative models to analyse solvent
effects in pure solvents which are based on empirical solvent polarity parameters, lack
general applicability. Moreover, the molecular basis of solvent effects remains unclear
because of the undefined physical significance of these polarity scales. Macroscopic
solvent parameters, derived from physical properties of the solvent give an unrealistic
picture of the reaction medium as a continuum without specific structure. Specific
interactions between solvent and reacting species, as well as the importance of the
structure of the solvent, are neglected. More sophisticated, theoretical approaches to
analyse solvent effects in pure solvents are either inaccessible or difficult to use for
practical problems.
Many chemical reactions are performed in mixtures of solvents. Particularly
solvent mixtures of water and an organic cosolvent are very popular. Quantitative
descriptions of solvent effects in mixtures of solvents are even more complicated than
those in the pure solvents. It is, for example, an impossible task to determine solvent
polarity parameters in every mixture of solvents. Very often therefore, the assumption
has been made that these solvent parameters depend linearly on the composition of
the mixture. Obviously, the occurence and consequences of preferential solvation are
not taken into account. The even more pronounced complexity of specific solutesolvent interactions is also fully neglected.
Patterns of organic reactivity in mixed aqueous solutions are particularly interesting. Kinetic data for reactions in water and in mixed aqueous solvents are often
intriguing and their interpretation is a real challenge. The study of organic reactivity in
water and in aqueous solutions has become more interesting since water has been
shown to induce high reaction rate constants as well as high selectivities for a number
of organic reactions, both homogeneous and heterogeneous (see Table 1-1).The low
solubility of organic reagents can be overcome by addition of organic cosolvents. The
consequences of addition of cosolvents for reactivity and selectivity of reactions in
water are unknown. A quantitative study of solvent effects on a series of organic
reactions in water and in mixed aqueous solvents, based on a general theory for
quantitative analysis of solvent effects in mixed solvents, would offer insight into the
molecular basis of rate effects on organic reactions in aqueous media. This knowledge
should enable organic chemists to select organic reactions, which can benefit from
mixed aqueous solvents with a suitable composition with respect to solubility, reactivity and selectivity, in a rational way. However, it is remarkable that no valid quantitative model exists for the analysis of solvent effects on reactions in mixed solvents.
I . Introduction Solvent effects on manic r e a c h in aquew~smirtwes
1.6 A h of this st&
The general aim of this study was to develop and test a new, simple, but general
theoretical model for the quantitative analysis of solvent effects in mixed solvents. An
important objective was to draw together transition state, theory and thermodynamic
formalism to describe thermodynamic properties of solutions. Following this approach,
three important demands, made with respect to a novel theoretical model for the
analysis of solvent effects in mixed solvents, can be met.
Kinetic medium effects in mixed solvents can be expressed in terms of thermodynamic parameters.
These
thermodynamic parameters can be determined by experimental techni(ii)
ques other than kinetic measurements.
(iii) The theoretical model enables a quantitative analysis of observed solvent effects
leading to further insight into the solute-solvent interactions which govern
solvent effects in mixed solvents.
(i)
A major incentive for the development of a new theoretical model for the
quantitative analysis of solvent effects on reactions in mixed solvents has been its
possible application to study solvent effects on reactions in mixed aqueous media. In
fact, this application would involve a rigorous test for the new approach. The second
aim of this study was, therefore, to critically appraise the developed theory by studying
the kinetics of, first, simple first-order processes and, later, of bimolecular reactions
and equilibria, in mixed aqueous solvents. The general strategy involved systematic
variation of the nature of the mixed aqueous solvent (i) by varying of the composition
of the mixed solvent and (ii) by varying the structure of the cosolvent(s). In addition,
different reaction types have been studied and the structure of the reacting molecules
has also been changed by changing substituents. The consequences for a quantitative
analysis of the observed solvent effects, based on the novel theoretical model, have
been examined. Concomittantly, the variation of the structure of the reactants
provides an opportunity for a detailed quantitative study of the contribution of
solvation effects to the overall substituent effects of alkyl groups on chemical reactivity
in mixed aqueous solvents. A challenging goal was found in the application of the
developed theory to elucidate the role of water, and eventually of the apolar cosolvents, in the spectacular rate enhancements of some organic reactions in aqueous
media.
1.7 Survey of the contents of thk thesis
Chapter 1 contains a general introduction in the field of qualitative and quantitative
methods for the analysis of solvent effects. After a brief historical overview, emphasis
is placed on recent methods to analyse solvent effects. In this context conventional
methods are critically discussed. The second part of the chapter is devoted to a
description of water and mixed aqueous solvents as reaction media. Attention is
focussed on intermolecular interactions in aqueous solvents. Hydrophobic effects are
1. Introduction Solvent effects on organic reactions in aqueous mirrures
clearly defined and recent theories on hydrophobic effects are discussed. Finally, the
incentives and aims of the study are summarised.
A general theoretical model for the analysis of solvent effects in mixed solvents is
reported in Chapter 2. In this chapter, kinetic theory and thermodynamic formalism to
describe thermodynamic properties of solutions are drawn together. This leads to
theoretical expressions which relate solvent effects in mixed solvents to the composition of the solvent. The general model is elaborated by using two alternative thermodynamic descriptions of the reaction medium, dependent on the composition of the
medium. Both methods are discussed in detail and are critically compared. Theoretical
expressions are derived for solvent effects on a simple unimolecular reaction in mixed
solvents. The expressions are modified in order to analyse solvent effects on solvolysis
reactions, bimolecular processes and chemical equilibria. Furthermore, the quantitative treatment for the analysis of solvent effects on Gibbs energies of activation is
extended to a quantitative analysis of enthalpies and entropies of activation in mixed
solvents. A general feature of all theoretical expressions derived is that they describe
the dependence of reactivity on the composition of the reaction medium in terms of
interactions of the (co)solvent(s) with the reactants and activated complex, respectively. These expressions form the basis of the second part of the thesis, and will be used
frequently.
In Chapter 3, solvent effects are described on the neutral hydrolysis of l-benzoyl3-phenyl-1,2,4-triazole in mixed aqueous solvents that contain monohydric and polyhydric alcohols. In the introduction, the vast amount of literature on solute-solute
interactions in dilute aqueous solutions is briefly reviewed and some important
features are discussed. The new theoretical model, as developed in Chapter 2, is
critically tested by analysing the solvent effects of 24 different mono- and polyhydric
alcohols on the rates of hydrolysis. The theoretical expression was found to describe
the experimental data very well. Particular attention has been paid to the applicability
of group additivity approaches for the analysis of solute-solute interactions. It was
observed that addivity schemes are only valid under strict conditions and deviation
from additivity is discussed in detail. In addition, the effect of urea on solvent effects
in mixed aqueous solvents was investigated. Urea reduces the solvent effects of apolar
cosolvents, whereas urea itself does not induce a significant solvent effect at all.
Solvent effects are expressed in terms of Gibbs energy parameters, describing solutesolute interactions in aqueous solutions, and the results are compared with literature
data for the analysis of solute-solute interaction in aqueous media. Emphasis has been
placed on the participation of the cosolvent in the solvation shell of the reactant and
the activated complex, accompanied by hydration shell overlap.
In the first part of Chapter 4, solvent effects on the Gibbs energy, the isobaric
enthalpy and entropy of activation of the neutral hydrolysis of p-methoxyphenyl
dichloroacetate in mixed aqueous solvents containing urea and alkyl-substituted ureas,
are quantitatively analysed. The theoretica1 model, developed in Chapter 2, is shown
to describe the dependence of the activation parameters on the composition of the
reaction medium. However, higher-order enthalpic and entropic interaction terms are
more important for the description of solute-solute interactions in dilute aqueous
solutions than higher order Gibbs energetic interaction terms. The origin of this
phenomenon is discussed in detail in terms of hydrophobic effects. In the second part
of Chapter 4, the theory is successfully applied in the quantitative analysis of solvent
1. Introduction Solvent EfJects on organic r e a c h in aqueous m h s
effects on the Diels-Alder reaction of methyl vinyl ketone with cyclopentadiene, the
keto-en01 equilibrium of 2,epentanedione and the intramolecular Diels-Alder reaction
of N-alkyl-N-furfurylmaleamicacid in mixed aqueous solvents.
A thorough study of the medium effect of ethanol and 1-propanol on the neutral
hydrolysis of 18 different l-acyl-3-alkyl-1,~4-triazolesis reported in Chapter 5. The
dependence of the solvent effect on the alkyl groups in the substrate was examined in
detail. The solvent effects depend critically on the substituent. This implies that the
substituent effects of alkyl groups are significantly affected by the composition of the
solvent. In the introduction conventional quantitative methods for analysing, understanding and predicting alkyl substituent effects in terms of substituent constants are
outlined and discussed. The results show that substituent effects of all@ groups on
reactions in aqueous media are strongly governed by solvation effects. It is argued that
efforts to describe steric, polar and inductive effects of alkyl substituents either include
a substantial contribution of solvation effects or are completely useless. The contribution of solvation to the substituent effect of alkyl groups on reaction rates of reactions
in aqueous media is explained in terms of "hydrophobic acceleration".
The main theme of Chapters 6 and 7 is the analysis of solvent effects on DielsAlder reactions in mixed aqueous solvents, containing monohydric alcohols across the
whole mole fraction range. The applicability is tested of the theoretical expression,
derived in Chapter 2, for a quantitative anaIysis of solvent effects in binary solvents.
Chapter 6 contains a quantitative study of solvent effects on the rate constants
and isobaric activation parameters for bimolecular Diels-Alder reactions of cyclopentadiene with alkyl vinyl ketones as well as with 5-substituted-1,4-naphthoquinonesin
mixed aqueous solvents. In addition, standard Gibbs energies of transfer of the
reactants, activated complex and products of the Diels-Alder reaction of alkyl vinyl
ketones and cyclopentadiene from 1-propanol to aqueous solutions of 1-propanol have
been determined and analysed.
Chapter 7 describes the synthesis and the intramolecular Diels-Alder reaction of
four N-alkyl-N-furfurylmaleamic acids. The intramolecular Diels-Alder process
undergoes a spectacular rate increase in aqueous reaction media. The solvent effects
appear to be very similar to solvent effects on the bimolecular process. Emphasis is
placed on solvent effects on the stereochemistry of the intramolecular cyclisation.
The solvent effects, reported in Chapters 6 and 7, are satisfactorily described by
the derived theoretical expressions. The spectacular rate effects of water on DielsAlder reactions are largely preserved in highly aqueous reaction media. Preferential
solvation of the reactants appears to diminish the rate effect of water in the presence
of higher concentrations of cosolvent molecules. The spectacular rate accelerations
are ascribed to the apparent decrease of the hydrophobic surface of the apolar
reactants during the activation process. This "hydrophobic acceleration" is a result of
"enforced hydrophobic interaction" of the reactants during the activation process. The
possibility of induction of a more polar activated complex in highly aqueous media is
tentatively suggested.
Chapter 8 evaluates the applicability, merits and shortcomings of the proposed
theoretical treatment of solvent effects in mixed aqueous solvents. In this thesis, the
dependence of solvent effects on reactivity of apolar organic reactants in water on the
concentration of cosolvents, has been mainly explained in terms of bulk and pairwise
hydrophobic interactions. Based on the quantitative analyses of these solvent effects a
1. Introduction Solvent effects on organic reactions in aqueous mixtwes
novel model is introduced for the description of hydrophobicity and hydrophobic
interactions. This model accounts for the most characteristic properties of hydrophobic effects. Finally, the use of water as a solvent for organic reactions is critically
discussed. It is shown that organic reactions can benefit from water as a solvent due
to the fact that reactive, hydrophobic species in water and highly aqueous media tend
to minimise their hydrophobic exposure to water of the hydrophobic groups during
the activation process. Reaction types are suggested which might be accelerated in
aqueous solutions.
A major part of the work described in this thesis either has already been published or will be published in the near f u t ~ r e ' ~ ~ - ~ ~ ~ .